Potent somatostatin undecapeptide agonists selective for somatostatin receptor 1 (sst1)

A family of analogues of des-AA(1,2,5)-[DTrp(8)/D2Nal(8)]-SRIF that contain a 4-(N-isopropyl)aminomethylphenylalanine (IAmp) at position 9 was identif ied that has high affinity and selectivity for human somatostatin receptor subtype 1 (sst1). The binding affinities of des-AA(1,2,5)- [DTrp(8),IAmp(9) ]-SRIF (c[H-Cys-Lys-Phe-Phe-DTrp-IAmp-Thr-Phe-Thr-Ser-Cys-OH], CH-275) (7), des-AA(1,5)-[Tyr(2),DTrp(8),IAmp(9)]-SRIF (CH-288) (16), des-AA(1,2,5)-[Ty r(7),DTrp(8),IAmp(9)]-SRIF (23), and des-AA(1,2,5)-[DTrp(8),IAmp(9),Tyr(11) ]-SRIF (25) are about 1/7, 1/4, 1/125, and 1/4 that of SRIF-28 (1) to sst1, respectively, about 1/65, 1/130, <1/1000, and <1/150 that of 1 to sst3, re spectively, and about or less than 1/1000 that of 1 to the other three huma n SRIF receptor subtypes. A substitution of DTrp(8) by D2Nal(8) in 7 to yie ld des-AA(1,2,5)-[D2Nal(8),IAmp(9)]-SRIF (13) and in 16 to yield des-AA(1,5 )-[Tyr(2),D2Nal(8),IAmp(9)] -SRIF (17) was intended to increase chemical st ability, selectivity, and affinity and resulted in two analogues that were less potent or equipotent with similar selectivity, respectively. Carbamoyl ation of the N-terminus as in des-AA(1,2,5)[DTrp(8),IAmp(9),Tyr(11)]-Cbm-SR IF (27) increased affinity slightly as well as improved selectivity. Monoio dination of 25 to yield 26 and of 27 to yield 28 resulted in an additional 4-fold increase in affinity at sst1. Desamination of the N-terminus of 17 t o yield 18, on the other hand, resulted in significant loss of affinity. At tempts at reducing the size of the ring with maintenance of selectivity fai led in that des-AA(1,4,5,13)-[Tyr(2),DTrp(8),IAmp(9)] -SRIF (33) and des-AA (1,4,5,6,12,13)- [Tyr(2),DTrp(8),IAmp(9)] -SRIF (34) progressively lost aff inity for all receptors. Both desAA(1,2,5)-[DTrp(8),IAmp(9),Tyr(11)]-Cbm-SR IF (27) and des-AA(1,2,5)- [DCys(3),DTrp(8),IAmp(9),Tyr(11)]-Cbm-SRIF (29) show agonistic activity in a cAMP assay; therefore, the structural basis fo r the agonist property of this family of analogues is not contingent upon t he chirality of the Cys residue at position 3 as shown to be the case in 18 -membered ring SRIF octapeptides. None of the high affinity structures desc ribed here showed receptor antagonism. We have prepared the radiolabeled de s-AA(1,2,5)- [DTrp(8),IAmp(9),(125)ITyr(11)]-SRIF (I-125-25) and des-AA(1,2 ,5)- [DTrp(8),IAmp(9), (125)ITyr(11)]-Cbm-SRIF (I-125-27), used them as in vitro tracers, and found them to be superior to des-AA(1,5)-[(125)ITyr(2),D Trp(8),IAmp(9)]-SRIF (I-125-16) for the detection of sst1 tumors in recepto r autoradiography studies.